U.S. patent number 4,767,874 [Application Number 06/905,456] was granted by the patent office on 1988-08-30 for stable freeze-dried preparations of an anticancer platinum complex.
This patent grant is currently assigned to Shionogi & Co., Ltd.. Invention is credited to Hirotane Kagawa, Kazuhiro Shima, Takayuki Tsukada.
United States Patent |
4,767,874 |
Shima , et al. |
August 30, 1988 |
Stable freeze-dried preparations of an anticancer platinum
complex
Abstract
Stable freeze-dried preparations of an anticancer platinum
complex, i.e. glycolato-cis-diammineplatinum (II), containing at
least one member selected from the group consisting of glucan,
water-soluble vinyl polymer, and polyethylene glycol as
stabilizers, are very useful in the treatment of various
cancers.
Inventors: |
Shima; Kazuhiro (Osaka,
JP), Tsukada; Takayuki (Hyogo, JP), Kagawa;
Hirotane (Osaka, JP) |
Assignee: |
Shionogi & Co., Ltd.
(Osaka, JP)
|
Family
ID: |
16634867 |
Appl.
No.: |
06/905,456 |
Filed: |
September 10, 1986 |
Foreign Application Priority Data
|
|
|
|
|
Sep 25, 1985 [JP] |
|
|
60-213180 |
|
Current U.S.
Class: |
556/137 |
Current CPC
Class: |
A61K
47/36 (20130101); A61K 47/32 (20130101); A61K
31/28 (20130101); A61K 47/10 (20130101); A61K
9/19 (20130101); A61P 35/00 (20180101) |
Current International
Class: |
A61K
9/19 (20060101); A61K 47/10 (20060101); A61K
47/32 (20060101); A61K 47/36 (20060101); A61K
31/28 (20060101); C07F 015/00 () |
Field of
Search: |
;556/137 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
0021009 |
|
Jan 1981 |
|
EP |
|
0057023 |
|
Aug 1982 |
|
EP |
|
0181166 |
|
May 1986 |
|
EP |
|
2306702 |
|
Nov 1976 |
|
FR |
|
2127291 |
|
Apr 1984 |
|
GB |
|
Primary Examiner: Shaver; Paul F.
Attorney, Agent or Firm: Wenderoth, Lind & Ponack
Claims
What is claimed is:
1. A freeze-dried preparation of glycolato-cis-diammineplatinum
(II) as the active ingredient containing at least one member
selected from the group consisting of glucan, water-soluble vinyl
polymer, and polyethylene glycol as a stabilizer.
2. A freeze-dried preparation claimed in claim 1 wherein the glucan
is water-soluble neutral glucan.
3. A freeze-dried preparation claimed in claim 1 wherein the glucan
is water-soluble modified starch or its derivative.
4. A freeze-dried preparation claimed in claim 1 wherein the glucan
is water-soluble cellulose derivative.
5. A freeze-dried preparation claimed in claim 2 wherein the
water-soluble neutral glucan is dextran, pullulan, or amylose.
6. A freeze-dried preparation claimed in claim 2 wherein the
water-soluble neutral glucan is dextran.
7. A freeze-dried preparation claimed in claim 3 wherein the
water-soluble modified starch or its derivative is dextrin,
cyclodextrin, soluble starch, or hydroxyethyl starch.
8. A freeze-dried preparation claimed in claim 4 wherein the
water-soluble cellulose derivative is methyl cellulose,
hydroxyethyl cellulose, hydroxypropyl methyl cellulose, or
carboxymethyl cellulose sodium salt.
9. A freeze-dried preparation claimed in claim 1 wherein the
water-soluble vinyl polymer is polyvinyl alcohol or polyvinyl
pyrrolidone.
10. A freeze-dried preparation claimed in claim 1 which contains
the stabilizer at a ratio of 0.05-5 weight-parts to 1 weight-part
of said active ingredient.
11. A freeze-dried preparation claimed in claim 1 which contains
the stabilizer at a ratio of 0.1-3 weight-parts to 1 weight-part of
said active ingredient.
Description
BACKGROUND OF INVENTION
1. Field of Invention
This invention relates to pharmaceutical preparations of
glycolato-cis-diammineplatinum (II) (hereinafter sometimes referred
to as the platinum compound) of the following formula: ##STR1##
which comprises at least one member selected from the group
consisting of glucan, water-soluble vinyl polymer and polyethylene
glycol as stabilizers.
2. Prior Arts
Cisplatin is one of the already-marketed cis-platinum compounds.
Stable cisplatin compositions were disclosed in JPN Unexamined
Patent Publication Nos. 54-157817 and 56-152415 and a method to
stabilize cisplatin by adding sodium chloride, mannitol and
variable-amount of alcohol was disclosed in JPN Unexam. Pat. Pub.
No. 59-78117.
SUMMARY OF THE INVENTION
Glycolato-cis-diammineplatinum (II) is very effective in the
treatment of various cancers but is unstable under usual storage
conditions. This invention provides stable freeze-dried
preparations of said anticancer complex containing at least one
member selected from the group consisting of glucan, water-soluble
vinyl polymer, and polyethylene glycol as stabilizers.
DESCRIPTION OF PREFERRED EMBODIMENT
1. Problem to be Solved
The platinum compound in this invention is a highly safe compound
with a potent anticancer action, as disclosed in JPN Unexam. Pat.
Pub. No. 59-222497. However, when formulated into freeze-dried
preparations for injection or for preservation by an ordinary
method, the platinum compound is so unstable as to turn gray or
brown in a comparatively short period of time during long-term
storage or under accelerated conditions. Decrease in the activity
or change in color is observed even if the preparation is in a form
of solution or powder filled in vials.
Therefore, the compound untreated has been deemed relatively low in
commercial value since it has been hard to manufacture, by a
conventional method, preparations of the platinum compound
preservable for a long period of time at room temperature.
2. Means to Solve the Problem
The present inventors have discovered that some water-soluble
polymers are effective in stabilizing the platinum compound; the
present invention is based on this findings.
The water-soluble polymers in this invention are glucan known as
natural polysaccharide or synthetic polymers. The glucan which may
be used in this invention includes, for example, water-soluble
neutral glucans such as dextran, pullulan, amylose, and the like;
water-soluble modified starches or its derivatives such as dextrin,
optionally methylated .alpha.-, .beta.-, or .gamma.-cyclodextrin,
soluble starch, hydroxyethyl starch, and the like; water-soluble
cellulose derivatives such as methyl cellulose (MC), hydroxyethyl
cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl
cellulose (HPMC), carboxymethyl cellulose sodium salt (CMC-Na), and
the like.
The synthetic polymers include, for example, water-soluble vinyl
polymers such as polyvinyl alcohol (PVA), polyvinylpyrrolidone
(PVP), and the like; the polyethylene glycol (PEG) having mean
molecular weight ranging 1500-9000; and the like.
All of these stabilizers may be used to attain the purpose of this
invention. Dextran, cyclodextrin, and pullulan are preferable in
view of the fact that the compositions of this invention are used
in intravenous injection. Amongst all, dextran having mean
molecular weight ranging 40,000 to 70,000 is most preferably
used.
Saccharides or sugar alcohols may be, if desired, added thereto as
well-known excipients, fillers, and tonicity agents.
Addition of these stabilizers is effective in preventing coloration
of the platinum compound. There is no upper limit in the ratio of
addition of these stabilizers to the platinum compound for
attaining the purpose of this invention. But it is not desirable to
use an excessive amount of additives in the case of pharmaceutical
products. Taking into account the operability in distributing the
composition into containers and the viscosity of the reconstituted
solution, the stabilizers should be used at a ratio of 0.05-5,
preferably 0.1-3, and more preferably 0.3-1 weight-parts to 1
weight-part of the platinum compound. Addition of the stabilizers
at a ratio below the lower limit as defined above is insufficient
to prevent the change in color.
Therefore, in order to prepare a stable freeze-dried preparation of
said platinum compound, it is appropriate to make a solution of the
platinum compound and stabilizers dissolved in an aqueous solvent,
then to freeze-dry it by a conventional method. Physical mixture of
the platinum compound with stabilizers is less effective in the
stabilization of the preparation.
Ordinarily, the freeze-drying is achieved by means of a tray
freeze-drying method, spray freeze-drying method, vial
freeze-drying method, etc., that is, the aforementioned mixture is
cooled, frozen, and then the moisture of the frozen product is
sublimed under a high vacuum to give the objective freeze-dried
preparation. For instance, vials containing the aqueous mixture so
prepared are placed in a freeze-drier for 5 to 72 hours, during the
course of which the shelf-temperature is lowered between about
-80.degree. C. and -20.degree. C., then raised and kept below about
-3.degree. C., more preferably below about -10.degree. C. under a
pressure of 0.005 to 1 mb, to give a freeze-dried preparation.
As is widely known, the platinum compound is soluble in water and
the preparation produced under sterile conditions can be used for
intravenous injection and is also suitable as a long-term
preservation form of bulk products. Preparations produced under
sterile conditions can be dissolved in distilled water for
injection, transfusion, etc. and intravenously administrated.
This invention is explained in more detail by the following
Examples, which are not intended to limit the scope of this
invention.
GENERAL PROCEDURE
A solution of glycolato-cis-diammineplatinum (II) (A mg) and
stabilizer (B mg; in dry weight) dissolved in 1 ml of distilled
water for injection is filtered through a 0.22 .mu.m pore membrane
filter to give a sterile solution, which is then distributed into
vials in a prefixed amount to each. The vials are placed in a
freeze-drier, cooled to about -40.degree. C. and kept at the same
temperature for about 3 hours. Then, after the temperature is
elevated up to about -10.degree. C. or below, practically entire
amount of the water is removed by sublimation under pressure of
about 0.1 mb. After completion of the sublimation, the vials are
warmed up to about 40.degree. C. and kept for 4 hours to give a
freeze-dried preparation.
EXAMPLE 1
A solution of 10 mg of glycolato-cis-diammineplatinum (II) and 5 mg
(in dry weight) of dextran 70 dissolved in 1 ml of distilled water
for injection is filtered through a 0.22 .mu.m pore membrane filter
to give a sterile solution, 5 ml each of which is distributed into
14 ml vials.
The vials are placed in a freeze-drier, cooled rapidly to about
-40.degree. C. and kept at the same temperature for further 1 hour
after the frozen aqueous layer (product temperaure) is cooled down
to -35.degree. C. or below. Then the temperature is elevated up to
about -10.degree. C. or below, and the moisture is sublimed under
pressure of about 0.1 mb. After completion of the sublimation, the
vials are warmed up to about 40.degree. C. and kept for 4 hours to
give a freeze-dried preparation. The preparation contains 50 mg of
glycolato-cis-diammineplatinum (II) per vial.
EXAMPLES 2-21
The following freeze-dried preparations (Table 1) were obtained
according to the general procedure.
The respective filtrates (1 ml each) are distributed into 3 ml
vials to give freeze-dried preparations containing 10 mg of
glycolato-cis-diammineplatinum (II) per vial.
TABLE 1 ______________________________________ Exam. Stabilizer Pt
compd. No. (B mg) (A mg) ______________________________________ 2
Dextran 40 (0.5) 10 3 Dextran 40 (1.0) 10 4 Dextran 40 (10.0) 10 5
Dextran 70 (1.0) 10 6 Dextran 70 (0.5) 10 7 Dextran 70 (1.0) 10 8
Dextran 70 (10.0) 10 9 Dextran 70 (40.0) 10 10 Dextran (mol. wt.
100,000-200,000) (10.0) 10 11 .alpha.-Cyclodextrin (10.0) 10 12
.beta.-Cyclodextrin (10.0) 10 13 Dextrin (10.0) 10 14 Pullulan
(PF-20) (10.0) 10 15 MC (15 cps) (10.0) 10 16 HPC (SL) (10.0) 10 17
HPMC (2906) (10.0) 10 18 CMC-Na (10 cps) (10.0) 10 19 PVA (PA-20)
(10.0) 10 20 PVP (K-90) (10.0) 10 21 PEG (6000) (10.0) 10
______________________________________
EXPERIMENT 1
Effect for preventing changes in color was observed on both powders
and solutions just after reconstituted of the preparations
manufactured in Examples 1 to 21 (Table 2). The reconstituted
solutions were so prepared that the final concentration of said
platinum compound reached 1% (w/v). The degrees of coloration
changes are shown as (-) to (+++) in the Table. In the same manner
as above, the reference compositions 1 and 2 were also observed for
comparison. The composition numbers shown below correspond to the
Example numbers.
NOTE 1
Reference composition 1: A physical mixture of dextran 70 (1
weight-part) with the platinum compound (1 weight-part).
Reference composition 2: A freeze-dried preparation of platinum
compound containing no stabilizers.
NOTE 2
(-) indicates no change in color was observed, (.+-.) a slight
change in color observed, and (+) to (+++) indicate changes in
color were getting stronger in the order given.
TABLE 2 ______________________________________ Compo- sition
Appearance (after a 10 day storage at 60.degree. C.) Tested Powder
Solution Reconstituted ______________________________________ 1
White (-) Colorless, Transparent (-) 2 White (.+-.) Colorless,
Transparent (.+-.) 3 White (-) Colorless, Transparent (-) 4 White
(-) Colorless, Transparent (-) 5 Gray (+) Red Purple Transparent
(+) 6 White (.+-.) Colorless, Transparent (.+-.) 7 White (-)
Colorless, Transparent (-) 8 White (-) Colorless, Transparent (-) 9
White (-) Colorless, Transparent (-) 10 White (-) Colorless,
Transparent (-) 11 White (-) Colorless, Transparent (-) 12 White
(-) Colorless, Transparent (-) 13 White (-) Colorless, Transparent
(-) 14 White (-) Colorless, Transparent (-) 15 White (-) Colorless,
Transparent (-) 16 Grayish brown (+) Reddish Brown, Transparent
(++) 17 Grayish brown (+) Reddish Brown, Transparent (++) 18 White
(-) Colorless, Transparent (-) 19 White (-) Colorless, Transparent
(-) 20 White (-) Colorless, Transparent (- ) 21 Gray (++) Red
Purple, Transparent (+) Ref. 1 Gray (++) Reddish Brown, Transparent
(+++) Ref. 2 Grayish brown (+++) Reddish Brown, Transparent (+++)
______________________________________
EXPERIMENT 2
The following compositions were examined with respect to decrease
in the potency of the platinum compound (Table 3). Table 3 shows
the remaining potency in each composition in percent and changes in
color by (-) to (+++).
TABLE 3 ______________________________________ 40.degree. C.
Composition 1 month after 2 month after 4 month after
______________________________________ 1 100.8 (-) 99.2 (-) 101.1
(-) 8 100.4 (-) 97.1 (-) 98.4 (-) 9 100.0 (-) 98.6 (-) 99.7 (-)
Ref. 1 99.5 (++) 99.4 (++) --
______________________________________
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